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Investigators are building an empirical evidence base for real-world data through large-scale emulation of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.
This is a non-randomized, non-interventional study that is part of the Randomized Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology (RCT-DUPLICATE) initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to assess the comparative effectiveness of
on cardiovascular outcomes in individuals typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes (T2DM) and overweight but might not meet the eligibility criteria of pivotal RCTs for each drug (SUSTAIN-6 and SURPASS-CVOT trials), used to support regulatory approval in patients at cardiovascular risk.Although many features of the target trials cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the target trial. Randomization cannot be achieved in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice.
The three database studies will be new-user active-comparative studies, conducted using 3 national United States claims databases, where investigators compare the effect of semaglutide vs sitagliptin (used as an active comparator placebo proxy), tirzepatide vs dulaglutide, and tirzepatide vs semaglutide on the composite end point of all-cause mortality, myocardial infarction, or stroke. Clinical guidelines during the study period recommended both tirzepatide and semaglutide for the same indications of glucose lowering and weight reduction.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Tirzepatide vs dulaglutide |
| |
| Cohort 2 | Semaglutide vs sitagliptin |
| |
| Cohort 3 | Tirzepatide vs semaglutide |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tirzepatide | Drug | New use of tirzepatide dispensing claim is used as the exposure. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Composite of all-cause mortality, myocardial infarction or stroke (Tirzepatide vs. dulaglutide) | To evaluate the comparative effect of tirzepatide vs dulaglutide on the composite of all-cause mortality, myocardial infarction, or death in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Composite of all-cause mortality, myocardial infarction or stroke (Injectable semaglutide vs sitagliptin) | To evaluate the comparative effect of injectable semaglutide vs sitagliptin on the composite of all-cause mortality, myocardial infarction, or death in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Composite of all-cause mortality, myocardial infarction or stroke (Tirzepatide vs injectable semaglutide) | To evaluate the comparative effect of tirzepatide vs semaglutide on the composite of all-cause mortality, myocardial infarction, or death in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Measure | Description | Time Frame |
|---|---|---|
| Individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke (Tirzepatide vs dulaglutide) | To evaluate the comparative effect of tirzepatide vs dulaglutide on the individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. |
| Measure | Description | Time Frame |
|---|---|---|
| Hernia (Tirzepatide vs dulaglutide) | To evaluate the effect of tirzepatide vs dulaglutide on negative control outcomes, including hernia in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
ELIGIBILITY FOR TIRZEPATIDE VS DULAGLUTIDE
Inclusion criteria
Exclusion Criteria:
ELIGIBILITY FOR SEMAGLUTIDE VS SITAGLIPTIN
Inclusion Criteria:
Exclusion Criteria:
ELIGIBILITY FOR TIRZEPATIDE VS SEMAGLUTIDE
Inclusion Criteria:
Exclusion Criteria:
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Individuals typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes mellitus and overweight.
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| Name | Affiliation | Role |
|---|---|---|
| Shirley Wang, PhD, ScM | Brigham and Women's Hospital | Principal Investigator |
| Nils Krüger, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Brigham and Women's Hospital | Boston | Massachusetts | 02120 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41207920 | Derived | Kruger N, Schneeweiss S, Desai RJ, Sreedhara SK, Kehoe AR, Fuse K, Hahn G, Schunkert H, Wang SV. Cardiovascular outcomes of semaglutide and tirzepatide for patients with type 2 diabetes in clinical practice. Nat Med. 2026 Jan;32(1):342-352. doi: 10.1038/s41591-025-04102-x. Epub 2025 Nov 9. |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Study Protocol and Statistical Analysis Plan | Aug 10, 2025 | Aug 22, 2025 | Prot_SAP_001.pdf |
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan: Amendment to Study Protocol and Statistical Analysis Plan | Oct 5, 2025 | Oct 13, 2025 | Prot_SAP_002.pdf |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D050177 | Overweight |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000098860 | Tirzepatide |
| C555680 | dulaglutide |
| C000591245 | semaglutide |
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D000067757 | Glucagon-Like Peptide-1 Receptor |
| D000067756 | Glucagon-Like Peptide Receptors |
| D043562 | Receptors, G-Protein-Coupled |
| D011956 | Receptors, Cell Surface |
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| Dulaglutide | Drug | New use of dulaglutide dispensing claim is used as the comparator. |
|
| Semaglutide | Drug | New use of semaglutide dispensing claim is used as the exposure/comparator. |
|
| Sitagliptin | Drug | New use of sitagliptin dispensing claim is used as the comparator. |
|
| 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Composite of all-cause mortality, hospitalization for heart failure, or urgent heart failure visits requiring intravenous diuretics (Tirzepatide vs dulaglutide) | To evaluate the comparative effect of tirzepatide vs dulaglutide on all-cause mortality, hospitalization for heart failure, or urgent heart failure visits in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Urinary tract infections (Tirzepatide vs dulaglutide) | To evaluate the comparative effect of tirzepatide vs dulaglutide on the safety outcome of urinary tract infections in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Serious bacterial infections (Tirzepatide vs dulaglutide) | To evaluate the comparative effect of tirzepatide vs dulaglutide on the safety outcome of serious bacterial infections in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Gastrointestinal adverse events (Tirzepatide vs dulaglutide) | To evaluate the comparative effect of tirzepatide vs dulaglutide on the safety outcome of gastrointestinal adverse events in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke (Injectable semaglutide vs sitagliptin) | To evaluate the comparative effect of injectable semaglutide vs sitagliptin on the individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Composite of all-cause mortality, hospitalization for heart failure, or urgent heart failure visits requiring intravenous diuretics (Injectable semaglutide vs sitagliptin) | To evaluate the comparative effect of injectable semaglutide vs sitagliptin on all-cause mortality, hospitalization for heart failure, or urgent heart failure visits in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Urinary tract infections (Injectable semaglutide vs sitagliptin) | To evaluate the comparative effect of injectable semaglutide vs sitagliptin on the safety outcome of urinary tract infections in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Serious bacterial infections (Injectable semaglutide vs sitagliptin) | To evaluate the comparative effect of injectable semaglutide vs sitagliptin on the safety outcome of serious bacterial infections in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Gastrointestinal adverse events (Injectable semaglutide vs sitagliptin) | To evaluate the comparative effect of injectable semaglutide vs sitagliptin on the safety outcome of gastrointestinal adverse events in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke (Tirzepatide vs injectable semaglutide) | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the individual components of the primary endpoint, i.e., all-cause mortality, myocardial infarction, or stroke in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Composite of all-cause mortality, hospitalization for heart failure, or urgent heart failure visits requiring intravenous diuretics (Tirzepatide vs injectable semaglutide) | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on all-cause mortality, hospitalization for heart failure, or urgent heart failure visits in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Urinary tract infections (Tirzepatide vs injectable semaglutide) | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the safety outcome of urinary tract infections in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Serious bacterial infections (Tirzepatide vs injectable semaglutide) | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the safety outcome of serious bacterial infections in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Gastrointestinal adverse events (Tirzepatide vs injectable semaglutide) | To evaluate the comparative effect of tirzepatide vs injectable semaglutide on the safety outcome of gastrointestinal adverse events in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Lumbar radiculopathy (Tirzepatide vs dulaglutide) |
To evaluate the effect of tirzepatide vs dulaglutide on negative control outcomes, including lumbar radiculopathy in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. |
| 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Hernia (Injectable semaglutide vs sitagliptin) | To evaluate the effect of semaglutide vs sitagliptin on negative control outcomes, including hernia in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Lumbar radiculopathy (Injectable semaglutide vs sitagliptin) | To evaluate the effect of semaglutide vs sitagliptin on negative control outcomes, including lumbar radiculopathy in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Hernia (Tirzepatide vs injectable semaglutide) | To evaluate the effect of tirzepatide vs injectable semaglutide on negative control outcomes, including hernia, in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| Lumbar radiculopathy (Tirzepatide vs injectable semaglutide) | To evaluate the effect of tirzepatide vs injectable semaglutide on negative control outcomes, including lumbar radiculopathy, in patients typically treated in clinical practice who are at cardiovascular risk with type 2 diabetes and overweight. | 1 day after cohort entry date until the first of outcome or censoring, up to 365 days |
| D004700 | Endocrine System Diseases |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D008565 | Membrane Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011964 | Receptors, Gastrointestinal Hormone |
| D018000 | Receptors, Peptide |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |